Primary open angle glaucoma is a significant cause of vision loss in the United States, with a prevalence projected to exceed 3 million by 2020. Worldwide, close to 60 million will be affected. The primary cell lost in glaucoma is the retinal ganglion cell (RGC) &its axons, which form the optic nerve. Elevated intraocular pressure (lOP) has been correlated with loss of RGCs &loss of RGCs correlates with loss of vision. Matrix metalloproteinase-9 (MMP-9) is a well characterized member of the metalloproteinase enzyme family that has been associated with remodeling &injury in both brain &retina. It has been correlated with loss of RGCs &change of lOP over time in other animal models of glaucoma. Our preliminary work suggests that experimentally induced chronic elevation of lOP correlates with increased MMP-9 &greater &more rapid loss of RGC axons, while MMP-9 knock-out shows slower &less severe loss of RGC axons. MMP-9 is expressed by numerous cell types, including macrophages &microglia. Activation of microglia &infiltration of macrophages has been shown in chronic neurodegenerative diseases ofthe brain &in other retinal pathologies. Response of local cells such as microglia to elevated lOP have been studied extensively. However, the possibility of a contribution of infiltrating macrophages remains to be clarified &provides a potentially new target for developing novel therapeutic approaches to glaucoma. This proposal will allow the PI to continue &exp&on her development as a clinician scientist begun under the auspices of the K12 program. This training will be elemental in the development ofthe PI as an independent investigator &will provide the first evidence of a systemic contribution to the pathology of glaucoma. In the near term, this proposal will allow the PI to further clarify mechanisms of MMP-9 &macrophage involvement in RGC death. It will also enable her to develop the preliminary data to support a future ROl submission. The long term potential of these investigations includes development of both diagnostic &therapeutic strategies applicable in the clinic for improved treatment of glaucoma patients. The proposed studies define a unique focus for the PI within neurodegeneration &glaucoma. RELEVANCE (See instructions): Glaucoma is a blinding disease that affects millions of people worldwide. Current treatment is limited to controlling eye pressure, which is not successful in all patients. New therapies to protect the optic nerve may significantly improve patient care.